The long range goals of the laboratory are to define in detail the antigenic requirements for induction, the specificity for H-2 and virus-associated determinants, and the genetic control of both the induction and the specificity of cytotoxic T lymphocyte (CTL) responses to weakly immunogenic antigens on syngeneic tumors induced by AKR/Gross MuLV. In addition we will investigate one possible mechanism of tumor escape from immune surveilance. Namely, some MuLV-induced tumors may be resistant to the ability of gamma interferon to augment cell surface H-2 expression. Although study of the high-leukemic AKR strain is the ultimate goal, this strain represents a very complex situation. Therefore, initial studies have dealt with the low-leukemic C57BL/6 (B6) strain which is genetically resistant to Gross virus-induced leukemia, but for which teh syngeneic tumor cell prototype for the definition of the Gross cell surface antigen (GCSA) exists. These studies resulted in the description of a scheme for raising H-2Kb restricted cytotoxic T cells specific for that subclass of endogenous AKR/Gross virus-induced leukemias which display GCSA. The present proposal would first further define this system so that a firm experimental basis would be obtained for the investigation of other strains of mice. Then, various F1, congenic, H-2 recombinant inbred and H-2Kb mutant mice, some of whose genotypes reflect differing contributions by donor strains of mice of high-leukemic phenotype, will be employed. Such an approach will extend our previous experiments which have shown the influence of both H-2 encoded genes and genes controlling viral antigen expression on antiviral CRL responsiveness. These studies thus ultimately serve as an approach towards the in-depth study of CTl responses in high-leukemic mice. Thus, a complicated, perhaps specifically immunodepressed system such as the AKR mouse can be systematically dissected by gradually building from a known positive system. With knowledge of the effects of individual genetic loci and viral influences, the AKR mouse can better be approached to determine if it is indeed nonresponsive to its spontaneously arising leukemias, and if so, how the system can be manipulated to promote an effective immune response. Definition of strageties to augment cell mediated responses to these weakly immunogenic antigens may have broad applicability to immune intervention to tumors in higher species.
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